Role of the Fanconi Anemia DNA Repair Pathway in Epidermal Stem and Progenitor Cells

项目摘要/摘要：人类皮肤和粘膜主要由角质形成细胞组成，角质形成细胞 在维护器官和组织屏障免受环境侮辱方面发挥关键作用。包括在这样的 侮辱是内源性和外源性DNA毒素，会导致基因组不稳定和DNA损伤。DNA修复 一旦DNA损伤发生，机制是关键的二级防御。而体内的所有细胞都有 进化出修复DNA损伤的复杂机制，缺陷修复的后果对 不同的器官，很可能植根于仍然知之甚少的发育过程。哪里都不是 器官特异性DNA修复的重要性比遗传的人类基因组不稳定更明显 失调性Fanconi贫血(FA)，体内每个细胞都无法修复某些类型的DNA 适当地损坏。该病的一个普遍的分子特征是缺乏FA DNA修复途径。 这种疾病的临床特征包括先天性异常，骨髓衰竭，奇怪的是，一种独特的 对角质形成细胞转化的敏感性。FA患者对鳞状细胞表现出极高的易感性 早期皮肤和粘膜癌，我们最近发现了新的粘连缺陷 在外观正常的患者皮肤中使用电子显微镜进行研究。FA通路在正常人群中的作用 角质形成细胞和发育起源的组织动态平衡缺陷和鳞癌易感性将是 在这里检查过了。根据初步数据，我假设FA途径的缺失损害了信号和屏障 体细胞表皮干细胞和祖细胞(ESPC)的功能以及这些异常反过来促进 皮肤3D工程模型中的组织缺陷以及最终的鳞癌易感性和进展。这些 假说将使用一种新的发育系统进行验证，在该系统中，诱导的多能干细胞产生 来自FA患者的诱导补充以重建FA途径功能并分化为 角质形成细胞和3D表皮。项目的所有实验元素都已到位，我期待着学习 这将使我能够全面了解导致以下问题的发展过程 有缺陷的体细胞EPC和由此产生的遗传性疾病易感性是坚实的学术职业基础。

Project Summary/Abstract: Human skin and mucosa are composed predominantly of keratinocytes, which play a critical role in maintaining organ and organismal barriers against environmental insults. Included in such insults are endogenous and exogenous DNA toxins that cause genome instability and DNA damage. DNA repair mechanisms are a critical secondary defense once DNA damage has occurred. While all cells in the body have evolved sophisticated mechanisms to repair DNA damage, the consequences of defective repair are distinct for different organs and are likely rooted in developmental processes that remain poorly understood. Nowhere is the importance of organ-specific DNA repair more apparent than in the inherited human genome instability disorder Fanconi Anemia (FA), wherein every cell in the body is incapable of repairing certain types of DNA damage properly. A universal molecular feature of the disease is the absence of the FA DNA repair pathway. Clinical features of the disease include congenital abnormalities, bone marrow failure and, curiously, a unique susceptibility to keratinocyte transformation. FA patients exhibit an extreme susceptibility to squamous cell carcinomas (SCCs) of the skin and mucosa early in life, and we have recently uncovered novel adhesion defects in normal-appearing patient skin using electron microscopic studies. The role of the FA pathway in normal keratinocytes and developmental origins for defective tissue homeostasis and SCC predisposition will be examined here. I hypothesize, based on preliminary data, that FA pathway loss impairs signaling and barrier functions of somatic epidermal stem and progenitor cells (ESPCs) and that these abnormalities, in turn, promote tissue defects in 3D engineered models of skin as well as ultimately SCC susceptibility and progression. These hypotheses will be tested using a novel developmental system wherein induced pluripotent stem cells generated from FA patients are inducibly complemented to reconstitute FA pathway function and differentiated into keratinocytes and 3D epidermis. All experimental elements of the projects are in place and I anticipate a learning experience which will allow me to gain a comprehensive understanding of developmental processes leading to defective somatic ESPCs and resulting inherited disease susceptibilities as a solid academic career foundation.